With an estimated 2.6 million new HIV infections in 2009, the world remains a long way from reaching the ambitious UNAIDS goal of zero new infections. In this context, prevention of HIV-1 transmission has been identified as a top Fiscal Year 2012 Trans-NIH AIDS Research Priority. In the wake of recent observational and randomized trial evidence that treatment provided to HIV-positive individuals can reduce transmission of the virus to their sex partners by as much as 96%, there is an urgent need for a new paradigm that redefines our understanding of transmission potential as it relates simultaneously to both sexual risk behavior and ART exposure. For HIV-positive women, who can now anticipate prolonged survival in the context of lifelong treatment, this will require an understanding of how transmission potential varies across the lifespan in relation to key reproductive health events including decisions about contraception, fertility desire, pregnancy, the post partum period, and menopause (hereafter, lifecourse events). Our objective in this multidisciplinary series of quantitative and qualitative studies is to characterize the presence, magnitude, and contextual basis of variations in HIV-positive Kenyan women's transmission potential in relation to these important lifecourse events. A prospective cohort design with collection of complementary behavioral and biological endpoints will provide strong evidence regarding the presence and temporal sequence of associations between lifecourse events and transmission potential, defined as unprotected sex in the setting of late ART refills. The open cohort study will include 360 HIV-positive Kenyan women who are offered ART in Mombasa and Nairobi. Participants will be recruited to represent three distinct and important risk groups; women in discordant couples, pregnant and post-partum women from maternal and child health clinics, and female sex workers. This diversity will provide substantial generalizability, as well s an opportunity to identify important differences in transmission potential between the three risk groups. In-depth interviews and focus group discussions will add to our understanding of the sociobehavioral context for changes in behavior. Our ability to leverage ongoing data collection from a cohort of HIV-positive women in Mombasa provides a unique advantage, as this will allow us to evaluate changes in transmission potential over more than 10 years in a subset of the study population. These studies will provide the most comprehensive data available to understand transmission potential in HIV-positive African women treated with ART. This research will directly improve public health, expanding our understanding of HIV prevention from a perspective that recognizes the potentially profound influence of HIV-positive women's reproductive lifecourse events on their transmission potential. These data are expected guide program implementation and inform development of a new generation of clinical trials to optimize prevention in an era where effective use of ART will take its place alongside condoms and abstinence as a cornerstone of prevention in positives. PUBLIC HEALTH RELEVANCE: This multidisciplinary study of HIV-positive Kenyan women will employ a rapidly evolving paradigm for understanding HIV transmission potential by employing simultaneous measurement of sexual risk behavior and adherence to antiretroviral therapy. Changes in transmission potential will be evaluated in terms of their relationship to women's key reproductive choices and events including contraception, fertility desire, pregnancy, the post-partum period, and menopause. These data will inform HIV prevention research and program implementation in the context of overwhelming recent evidence that antiretroviral therapy should be recognized alongside condoms and abstinence as a cornerstone of prevention in positives.